PROJECT SUMMARY Chronic hepatitis B virus (HBV) infections are recognized as major global health concern. Chronic HBV infection affects 240 million people worldwide, and 650,000 die annually from associated liver complications. Despite this high morbidity and mortality, animal models of HBV infection are severely limited; a situation that has been exacerbated by the recent removal of all NIH funding for chimpanzee research. Thus, there remains an urgent need to develop a novel, physiologically relevant primate model of HBV infection. Here, we present the first rhesus macaque model of HBV infection and propose two distinct ways to improve this model by increasing the permanent expression of the HBV receptor, NTCP, on liver hepatocytes. We believe that our new rhesus macaque model of HBV infection will be on the forefront of HBV research, and is becoming available at a crucial time where efforts are now turning towards cure strategies for HBV. Given the urgent need for tractable animal models of HBV infection, we believe the research proposed herein to be of the highest significance.